Association between polymorphism in regulatory region of gene encoding tumour necrosis factor alpha and risk of Alzheimer's disease and vascular dementia: a case-control study

Background Deposition of beta -amyloid in the brains of patients with Alzhe imer's disease is thought to precede a chain of events that leads to an inf lammatory response by the brain. We postulated that genetic variation in th e regulatory region of the gene for the proinflammatory cytokine tumour nec rosis factor alpha (TNF-alpha) leads to increased risk of Alzheimer's disea se and vascular dementia. Methods A polymorphism in the regulatory region of the TNF-alpha gene was a nalysed in a case-control study. The polymorphism (C-850T) was typed in 242 patients with sporadic Alzheimer's disease, 81 patients with vascular deme ntia, 61 stroke patients without dementia, and 235 normal controls. These g roups of individuals were also genotyped for the apolipoprotein E polymorph ism, and the vascular dementia and stroke groups were typed at the HLA-DR l ocus. Findings The distribution of TNF-alpha genotypes in the vascular dementia g roup differed significantly from that in the stroke and normal control grou ps, giving an odds ratio of 2.51 (95% CI 1.49-4.21) for the development of vascular dementia for individuals with a CT or TT genotype. Logistic regres sion analysis indicated that the possession of the T allele significantly i ncreased the risk of Alzheimer's disease associated with carriage of the ap olipoprotein E epsilon4 allele (odds ratio 2.73 [1.68-4.44] for those with apolipoprotein E epsilon4 but no TNF-alpha T, vs 4.62 [2.38-8.96] for those with apolipoprotein E epsilon4 and TNF-alpha T; p=0.03). Interpretation Possession of the TNF-alpha T allele significantly increases the risk of vascular dementia, and increases the risk of Alzheimer's disea se associated with apolipoprotein E. Although further research is needed, t hese findings suggest a potential role for anti-inflammatory therapy in vas cular dementia and Alzheimer's disease, and perhaps especially in patients who have had a stroke.